An engineered chimeric toxin that cleaves activated mutant and wild-type RAS inhibits tumor growth.
An engineered chimeric toxin that cleaves activated mutant and wild-type RAS inhibits tumor growth.
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一种工程嵌合毒素可以裂解激活的突变型和野生型 RAS，从而抑制肿瘤生长。
DOI：
10.1073/pnas.2000312117
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发表时间：
2020
影响因子：
11.1
通讯作者：
Satchell,KarlaJF
中科院分区：
文献类型：
--
作者：
Vidimar,Vania;Beilhartz,GregL;Park,Minyoung;Biancucci,Marco;Kieffer,MatthewB;Gius,DavidR;Melnyk,RomanA;Satchell,KarlaJF
尽管经过近四十年的努力，使用小分子方法广泛抑制致癌RAS已被证明是一个重大挑战。在这里，我们描述了一种泛RAS生物抑制剂的开发，该抑制剂由RAS-RAP 1特异性内肽酶与白喉毒素的蛋白质递送机制融合组成。我们表明，这种工程嵌合毒素不可逆地切割和灭活细胞内RAS在低皮摩尔浓度终止下游信号在受体承载细胞。此外，我们证明了在野生型或mukaryoRAS驱动的三种小鼠异种移植模型中的体内靶向接合和肿瘤负荷的降低。通过受体介导的机制细胞内递送有效的抗RAS生物制剂代表了开发针对广泛癌症的RAS治疗剂的有希望的方法。
Despite nearly four decades of effort, broad inhibition of oncogenic RAS using small-molecule approaches has proven to be a major challenge. Here we describe the development of a pan-RAS biologic inhibitor composed of the RAS-RAP1–specific endopeptidase fused to the protein delivery machinery of diphtheria toxin. We show that this engineered chimeric toxin irreversibly cleaves and inactivates intracellular RAS at low picomolar concentrations terminating downstream signaling in receptor-bearing cells. Furthermore, we demonstrate in vivo target engagement and reduction of tumor burden in three mouse xenograft models driven by either wild-type or mutantRAS. Intracellular delivery of a potent anti-RAS biologic through a receptor-mediated mechanism represents a promising approach to developing RAS therapeutics against a broad array of cancers.